Treatment of dyskinesia

ABSTRACT

The present invention relates to the treatment of dyskinesia with compounds of General Formula (I) such as topiramate. The compound may be topiramate or a derivative thereof. The dyskinesia may be associated with a basil ganglia-related movement disorder such as parkinsonism and may also arise as a side-effect of other therapeutic agents (e.g. L-DOPA).

The present invention relates to the treatment of dyskinesias.

Dyskinesias are abnormal involuntary movement disorders. The abnormalmovements may manifest as chorea (involuntary, rapid, irregular, jerkymovements that may affect the face, arms, legs, or trunk), ballism(involuntary movements similar to chorea but of a more violent andforceful nature), dystonia (sustained muscle contractions, usuallyproducing twisting and repetitive movements or abnormal postures orpositions) or athetosis (repetitive involuntary, slow, sinuous, writhingmovements, which are especially severe in the hands).

Movement and other disorders due to dysfunction of the basal ganglia andrelated brain structures are of major socio-economic importance. Suchdisorders can occur as a consequence of inherited or acquired disease,idiopathic neurodegeneration or they may be iatrogenic. The spectrum ofdisorders is very diverse, ranging from those associated with poverty ofmovement (akinesia, hypokinesia, bradykinesia) and hypertonia (e.g.Parkinson's disease, some forms of dystonia) to the involuntary movementdisorders (hyperkinesias or dyskinesias e.g. Huntington's disease,levodopa-induced dyskinesia, ballism, and some forms of dystonia).

Parkinsonism is a well known movement disorder comprising a syndromecharacterised by slowness of movement (bradykinesia), rigidity and/ortremor. Parkinsonian symptoms are seen in a variety of conditions, mostcommonly in idiopathic parkinsonism (i.e., Parkinson's disease) but alsofollowing treatment of schizophrenia, exposure to toxins/drugs and headinjury. In Parkinson's disease the primary pathology is degeneration ofdopaminergic neurons of the substantia nigra, pars compacta.

The most widely used symptomatic treatments for parkinsonism usedopamine-replacing agents (e.g. L-DOPA and dopamine receptor agonists).One common way in which dyskinesias arise is as a side-effect ofdopamine replacement therapy for parkinsonism or other basalganglia-related movement disorders. Dyskinesia can be seen either whenthe patient is undergoing dopamine-replacement therapy (in the case ofchorea and/or dystonia) or even when off therapy (when dystonia isprevalent). Ultimately, these side-effects severely limit the usefulnessof dopaminergic treatments.

Another problem associated with dopamine-replacement agents (e.g. L-DOPAand dopamine receptor agonists) is the “wearing-off” of theanti-parkinsonian efficacy of the treatment.

Another common cause of dyskinesias is the treatment of psychosis withneuroleptic drugs—this is known as tardive dyskinesia.

Dyskinesia also occurs in many other conditions including:

Huntington's disease

idiopathic dystonia

Tourette syndrome

“off” dystonia in parkinsonism

ballism

senile chorea

Knowledge of the pathophysiological mechanisms that underlie thesedisorders makes indicate that similar mechanisms mediate disorderscharacterized by either hyperkinesias or dyskinesias. It is to beexpected, therefore, that treatments that are effective in one form ofdyskinesia will be beneficial in dyskinesias of different aetiology.

Many attempts have been made to develop agents that will prevent thedevelopment of, and/or treat, dyskinesias although such attempts havemet with limited success. There is, therefore, a need to develop ways bywhich dyskinesias may be treated.

According to a first aspect of the present invention there is provided ause of a compound of general formula I:

-   -   wherein X is O or CH₂;    -   R₂, R₃, R₄ and R₅ are independently H, lower alkyl and R₂ and R₃        and/or R₄ and R₅ together may be a group of the following        formula (II):        -   wherein R₆ and R₇ are the same or different and are H, lower            alkyl or are alkyl and are joined to form a cyclopentyl or            cyclohexyl ring;            -   in the manufacture of a medicament for the treatment of                dyskinesia.

According to second aspect of the present invention there is provided amethod of treating dyskinesia in a subject which comprises administeringto the subject a therapeutically effective amount of a compound ofgeneral formula I.

By “dyskinesia” we mean abnormal involuntary movements that areassociated with disorders of brain regions known as the basal ganglia.The dyskinesia may be a “levodopa-induced dyskinesia” that arises is acomplication of the treatment of Parkinson's disease (the most commonbasal ganglia disease). Dyskinesia can physically manifest in two forms,chorea and dystonia. Chorea consists of involuntary, continuous,purposeless, abrupt, rapid, brief, unsustained and irregular movementsthat flow from one part of the body to another. Dystonia refers tosustained muscle contractions that cause twisting and repetitivemovements or abnormal postures.

Dyskinesias may be distinguished from ataxia or catalepsy. Ataxia isusually associated with disorders of a part of the brain called thecerebellum, or its connections. It is characterised by poor motorcoordination. There is a staggering gait (walk) and slurred speech,which may make the person appear “drunk”. Catalepsy is, again, adifferent condition that is impossible to confuse with dyskinesias. Itis usually associated with psychotic disorders. It is characterized byinactivity, decreased responsiveness to stimuli, and a tendency tomaintain an immobile posture. The limbs tend to remain in whateverposition they are placed. Thus, the terms dyskinesia (including choreaand dystonia), ataxia and catalepsy refer to distinct and separatedisorders. They have different physical manifestations and differentcauses.

The present invention is based upon research conducted by the inventorsrelating to the activity of anticonvulsant sulphamates of generalformula I. To their surprise they found that such compounds haveefficacy for reducing dyskinesias.

Preferred compounds of general formula I are disclosed in detail in U.S.Pat. No. 4,582,916, U.S. Pat. No. 4,5123,006, U.S. Pat. No. 6,420,369,U.S. Pat. No. 6,559,293, U.S. Pat. No. 6,583,172 and EP-B-0,138,441. Thecompounds disclosed in these documents may be used according to thepresent invention and are incorporated herein by reference. Accordinglypreferred compounds that may be used according to the invention include:(tetrahydro-2H-pyran-2-yl)methane sulphamate;2,3:4,5-bis-O-(1-methylethyidene)-β-D-fructopyranose sulphamate (seebelow); or 2,3:4,5-bis-O-(1-methylethyidene)-β-D-fructopyranosemethylsyulphamate.

A most preferred compound is Topiramate or a functional analogue orderivative thereof.

Topiramate is a sulfamate-substituted monosaccharide that is intendedfor use as an antiepileptic drug. Topiramate is designated chemically as2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate.Topiramate is sold under the registered trademark “Topamax®”. Topiramatehas the following structural formula:

Topiramate is a white crystalline powder with a bitter taste. Topiramateis most soluble in alkaline solutions containing sodium hydroxide orsodium phosphate and having a pH of 9 to 10. It is freely soluble inacetone, chloroform, dimethylsulfoxide, and ethanol. The solubility inwater is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramatehas the molecular formula C₁₂H₂₁NO₈S and a molecular weight of 339.36.

The use of compounds according to the invention for the treatment ofdyskinesias is an entirely novel invention. The basic neural mechanismswhich underlie epilepsy and dyskinesias are different. One would notexpect compounds such as topiramate to be effective in dyskinesias andthis, therefore, represents an inventive step.

Compounds according to the invention and compositions containing suchcompounds may be used to treat many types of dyskinesia. For instancethe compounds may be used to treat dyskinesias and hyperkinesiasassociated with conditions such as Huntington's disease, idiopathictorsion dystonia, tardive dyskinesia, Tourette syndrome and mostparticularly for dyskinesia associated with movement disorders such asparkinsonism (e.g. idiopathic Parkinson's disease, post-encephaliticparkinsonism or parkinsonism resulting from head injury), treatment ofschizophrenia, drug intoxication, the effect of toxins and the like.

A clinical trial of topiramate in the condition known as essentialtremor has recently been reported (Connor, G S, Neurology 2002;59:132-134) in which a mean improvement in tremor of 25% was recorded.It is important, therefore, to draw the distinction between this reportand the present invention.

Firstly, essential tremor is not related to the movement disorders whichare the subject of the present claims. Specifically, it is not relatedto Parkinson's disease, even though tremor may be present as a part ofthe classical triad of symptoms in the latter condition (Burne et al; JClin Neurosci., 2002; 9: 237-242) nor is it related to conditions suchas Huntington's disease, Wilson's disease, progressive supranuclearpalsy (PSP), dystonia, etc.

Essential tremor differs from Parkinson's disease in many ways.Importantly, there is no known neuropathology in essential tremor,whereas the pathological basis of Parkinson's disease is wellestablished to be degeneration of the substantia nigra, pars compacta ofthe midbrain. So far as they are known, the two conditions are mediatedby different brain mechanisms. Furthermore, the two conditions have adifferent pharmacological profile. For example, L-DOPA, which is used totreat Parkinson's disease is of no value in treating essential tremor.On the other hand, essential tremor often responds to low doses ofalcohol, which Parkinson's disease does not.

Secondly, the present invention relates not to the treatment ofParkinson's disease itself but dyskinesias which develop as acomplication of long-term conventional treatment with L-DOPA or dopamineagonists. There is no evidence that essential tremor and dyskinesias arein any way related in terms of their cause, the brain pathways involvedor their clinical pharmacological profile.

Compounds according to the invention are useful for treatment ofdyskinesias which arise as a side-effect of other therapeutic agents.For instance, topiramate is useful for the treatment of dyskinesiaassociated with L-DOPA treatment of parkinsonism or Parkinson's disease.

Levodopa is an aromatic amino acid. The chemical name of levodopa orL-DOPA is (−)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. L-DOPAhas the molecular formula C₉H₁₁NO₄ and a molecular weight of 197.2.Chemically, levodopa is (−)-3-(3,4-dihydroxy-phenyl)-L-alanine. It is acolorless, crystalline compound, slightly soluble in water and insolublein alcohol. L-DOPA has the following structural formula:

Because L-DOPA is an amino acid, it is commonly administered to patientsin combination with carbidopa for the treatment of Parkinson's diseaseand syndrome. The chemical name for carbidopa is(−)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acidmonohydrate. Carbidopa has the empirical formula C₁₀H₁₄N₂O₄.H₂O and amolecular weight of 244.3. Anhydrous carbidopa has a molecular weight of226.3. Sinemet® is a combination of carbidopa and levodopa for thetreatment of Parkinson's disease and syndrome. Sinemet® is described inU.S. Pat. Nos. 4,832,957 and 4,900,755, the contents of which are hereinincorporated by reference. The structural formula of carbidopa is:

In addition, the compounds according to the invention are useful for thetreatment of dyskinesias associated with ropinirole treatment.Ropinirole is a non-ergoline dopamine agonist sold under the trademarkRequip®. Ropinirole is the hydrochloride salt of4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochlorideand has an empirical formula of C₁₆H₂₄N₂O.HCl. The molecular weight ofropinirole is 296.84 (260.38 as the free base). Ropinirole is describedin U.S. Pat. Nos. 4,452,808 and 4,824,860, the contents of which arehereby incorporated by reference. The structural formula of ropiniroleis:

The compounds according to the invention are also useful for thetreatment of dyskinesias associated with pramipexole treatment. Thechemical name of pramipexole is(S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino) benzothiazoledihydrochloride monohydrate. Pramipexole dihydrochloride is sold underthe trademark Mirapex®. Pramipexole dihydrochloride has the empiricalformula C₁₀H₁₇N₃S.2HCl.H₂O and a molecular weight of 302.27. Thesynthesis of pramipexole is described in U.S. Pat. Nos. 4,843,086 and4,886,812, the contents of which are herein incorporated by reference.The structural formula of pramipexole dihydrochloride is:

The compounds may also be used for the treatment of dyskinesiasassociated with cabergoline treatment. The chemical name for cabergolineis 1-adamantanamine hydrochloride. It has a molecular weight of 187.71and a molecular formula of C₁₀H₁₈NCl. The structural formula ofcabergoline is:

The compounds may also be used for the treatment of dyskinesiasassociated with bromocriptine treatment. Bromocriptine mesylate is soldunder the trademark Parlodel®. The chemical name for bromocriptinemesylate is Ergotaman-3′,6′,18-trione,2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)-,(5′a)-monomethanesulfonate. The molecular weight of bromocriptinemesylate is 750.70 and it has an empirical formula ofC₃₂H₄₀BrN₅O₅.CH₄SO₃. The structural formula of bromocriptine mesylateis:

The compounds may also be used for the treatment of dyskinesiasassociated with lisuride treatment. The chemical name for lisuride isR(+)-N′-[(8α)-9,10-Didehydro-6-methylergolin-8-yl]-N,N-diethylureahydrogen maleate. Lisuride has a molecular weight of 338.45 and theempirical formula C₂₀H₂₆N₄O. The structural formula of lisuride is:

The compounds may also be used for the treatment of dyskinesiasassociated with pergolide treatment. The chemical name of pergolidemesylate is 8β-[(Methylthio)methyl]-6-propylergolinemonomethanesulfonate. Pergolide mesylate is sold under the trademarkPermax®. Permax has the empirical formula C₁₉H₂₆N₂S.CH₄O₃S and amolecular weight of 410.59. The synthesis of pergolide mesylate isdescribed in U.S. Pat. Nos. 4,797,405 and 5,114,948, the contents ofwhich are herein incorporated by reference. The structural formula ofpergolide mesylate is:

The compounds may also be used for the treatment of dyskinesiasassociated with apomorphine treatment. Apomorphine has the empiricalformula C₁₇H₁₇NO₂ and a molecular weight of 267.33. The structuralformula of apomorphine is:

It is preferred that dyskinesias associated with the abovementionedagents are treated with topiramate. In a specific embodiment of thepresent invention, topiramate is used for the treatment of dyskinesiaassociated with L-DOPA or apomorphine treatment.

The compounds are particularly useful for treating dyskinesia caused byagents used to treat movement disorders such as parkinsonism. In thisrespect a use of the compositions is in the treatment of dyskineticside-effects associated with L-DOPA or dopamine agonist therapy forparkinsonism.

The compounds may be used to treat existing dyskinesias but may also beused when prophylactic treatment is considered medically necessary, forinstance, when it is considered necessary to initiate L-DOPA therapy andit is feared that dyskinesias may develop.

The compounds may be used to treat dyskinesia as a monotherapy (i.e.,use of the compound alone); as an adjunct to compositions to preventdyskinetic side-effects caused by the composition (e.g. as an adjunct toL-DOPA or apomorphine given to treat parkinsonian patients) oralternatively the compounds may be given in combination with othertreatments which also reduce dyskinesia (e.g. μ-opioid receptorantagonists, α₂-adrenoreceptor-antagonists, cannabinoid CB₁-antagonists.NMDA receptor-antagonists, cholinergic receptor-antagonists, histamineH3-receptor agonists, and globus pallidus/subthalamic nucleuslesion/deep brain stimulation).

The compounds may also be used as an adjunct or in combination withknown therapies. For instance, we have found that the combination ofL-DOPA with topiramate results in movement disorders such as Parkinson'sdisease being treated with significantly reduced dyskineticside-effects.

The compounds may also be used in combination with a known neurolepticto treat patients suffering from tardive dyskinesia. The termneuroleptic refers to the effects on cognition and behavior ofantipsychotic drugs that reduce confusion, delusions, hallucinations,and psychomotor agitation in patients with psychoses. There is anaturally occurring chemical, a neurotransmitter, in the brain calleddopamine. Dopamine is the chemical messenger in the brain mainlyinvolved with thinking, emotions, behavior and perception. In someillnesses, dopamine may be overactive and upsets the normal balance ofchemicals in the brain. This excess dopamine helps to produce some ofthe symptoms of the illness. The main effect that these drugs have is toblock some dopamine receptors in the brain, reducing the effect ofhaving too much dopamine and correcting the imbalance. This reduces thesymptoms caused by having too much dopamine.

Neuroleptic drugs are a class of antipsychotics. Examples of neurolepticcompounds include: haloperidol (Haldol), chlorpromazine (Thorazine),thioridazine (Mellaril), risperidone (Risperdal), quetiapine (Seroquel),olanzapine (Zyprexa), clozapine (Clozaril), amisulpride (Solian),sertindole (Serdolect), zotepine (Zoleptil), Thiothixene (Navane),Molidone (Moban), Loxapine (Loxitane), Prochlorperazine (Compazine),Trifluoperazine (Stelazine), Perphenazine (Trilafon), and Metaclopramide(Reglan).

Haloperidol has a molecular formula of C₂₁H₂₃ClFNO₂ and a molecularweight of 375.8696 g/mol. Haloperidol is also referred to as Haldol;4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4′-fluorobutyrophenone;gamma-(4-(para-Chlorophenyl)-4-hydroxypiperidino)-para′-fluorobutyrophenone;and Serenace.

Chlorpromazine hydrochloride, a phenothiazine derivative, has a chemicalformula of 2-chloro-10-[3(-dimethylamino) propyl] phenothiazinemonohydrochloride. Chlorpromazine hydrochloride has the molecularformula: C₁₇H₁₉ClN₂S.HCl and a molecular weight of 355.33.

SEROQUEL® (quetiapine fumarate) is an antipsychotic drug belonging to anew chemical class, the dibenzothiazepine derivatives. The chemicaldesignation of quetiapine fumarate is 2-[2-(4-dibenzo [b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1)(salt). Quetiapine fumarate is present in tablets as the fumarate salt.All doses and tablet strengths are expressed as milligrams of base, notas fumarate salt. Quetiapine fumarate has a molecular formula ofC₄₂H₅₀N₆O₄S₂.C₄H₄O₄ and a molecular weight of 883.11 (fumarate salt).

The chemical name for clozapine is8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.Clozapine is a an atypical antipsychotic drug which is a tricyclicdibenzodiazepine derivative. Clozapine is sold under the trademark“CLOZARIL®”. Clozapine has a molecular weight of 326.83 and a molecularformula of C₁₈H₁₉ClN₄.

The chemical name of trifluoperazine hydrochloride is10-[3-(4-methyl-1-piperazinyl) propyl]-2-(trifluoromethyl) phenothiazinedihydrochloride. Trifluoperazine has a molecular weight of 480.43 and amolecular formula of C₂₁H₂₄F₃N₃S.2HCl.

Metoclopramide hydrochloride is a white crystalline, odorless substance,freely soluble in water. The chemical name of metoclopramide is4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamidemonohydrochloride monohydrate. Metoclopramide has a molecular weight of354.3.

Fluphenazine hydrochloride is a trifluoro-methyl phenothiazinederivative intended for the management of schizophrenia. The chemicalname of fluphenazine is 4-[3-[2-(Trifluoro-methyl) phenothiazin-10-yl]propyl]-1-piperazineethanol dihydrochloride. The molecular formular offluphenazine is C₂₂H₂₆F₃N₃OS.2HCl and its molecular weight is 510.44.

The compositions of the invention may take a number of different formsdepending, in particular on the manner in which the composition is to beused. Thus, for example, the composition may be in the form of a powder,tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray,micelle, transdermal patch, liposome or any other suitable form that maybe administered to a person or animal. It will be appreciated that thevehicle of the composition of the invention should be one which is welltolerated by the subject to whom it is given and enables delivery of thecompounds to the brain.

The composition of the invention may be used in a number of ways. Forinstance, systemic administration may be required in which case thecompound may be contained within a composition which may, for example,be ingested orally in the form of a tablet, capsule or liquid.Alternatively the composition may be administered by injection into theblood stream. Injections may be intravenous (bolus or infusion) orsubcutaneous (bolus or infusion). The compounds may be administered byinhalation (e.g. intranasally).

The compounds may also be administered centrally by means ofintracerebral, intracerebroventricular or intrathecal delivery.

The compound may also be incorporated within a slow or delayed releasedevice. Such devices may, for example, be inserted on or under the skinand the compound may be released over weeks or even months. Such adevice may be particularly useful for patients with long-term dyskinesiasuch as patients on continuous L-DOPA therapy for the treatment ofparkinsonism. The devices may be particularly advantageous when acompound is used which would normally require frequent administration(e.g. at least daily ingestion of a tablet or daily injection).

It will be appreciated that the amount of a compound required isdetermined by biological activity and bioavailability which in turndepends on the mode of administration, the physicochemical properties ofthe compound employed and whether the compound is being used as amonotherapy or in a combined therapy. The frequency of administrationwill also be influenced by the above mentioned factors and particularlythe half-life of the compound within the subject being treated.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

Known procedures, such as those conventionally employed by thepharmaceutical industry (e.g. in vivo experimentation, clinical trials,etc.), may be used to establish specific formulations of compositionsand precise therapeutic regimes (such as daily doses of the compoundsand the frequency of administration).

Generally, a daily dose of between 0.01 μg/kg of body weight and 1.0g/kg of body weight of a compound (e.g. topiramate) may be used for thetreatment of dyskinesia depending upon which specific compound is used.More preferably, the daily dose is between 0.01 mg/kg of body weight and100 mg/kg of body weight.

Daily doses may be given as a single administration (e.g. a daily tabletfor oral consumption or as a single daily injection). Alternatively, thecompound used may require administration twice or more times during aday. As an example, topiramate for treating L-DOPA induced dyskinesia inpatients with Parkinson's disease may be administered as two (or moredepending upon the severity of the dyskinesia) daily doses of between 25mgs and 5000 mgs in tablet form. A patient receiving treatment may takea first dose upon waking and then a second dose in the evening (if on atwo dose regime) or at 3 or 4 hourly intervals thereafter.Alternatively, a slow release device may be used to provide optimaldoses to a patient without the need to administer repeated doses.

This invention further provides a pharmaceutical composition comprisinga therapeutically effective amount of the compound of the invention anda pharmaceutically acceptable vehicle. In one embodiment, the amount ofthe compound (e.g. topiramate) is an amount from about 0.01 mg to about800 mg. In another embodiment, the amount is from about 0.01 mg to about500 mg. When the compound is topiramate, the amount of topiramate may bean amount from about 0.01 mg to about 250 mg; preferably about 0.1 mg toabout 60 mg; and more preferably about 1 mg to about 20 mg.

In a further embodiment, the vehicle is a liquid and the composition isa solution. In another embodiment, the vehicle is a solid and thecomposition is a tablet. In a further embodiment, the vehicle is a geland the composition is a suppository.

This invention provides a pharmaceutical composition made by combining atherapeutically effective amount of a compound of general formula I anda pharmaceutically acceptable vehicle.

Compounds of general formula I are preferably combined with apharmaceutically acceptable vehicle prior to administration.

This invention provides a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount of acompound of general formula I and a pharmaceutically acceptable vehicle.

In the subject invention a “therapeutically effective amount” is anyamount of a compound or composition which, when administered to asubject suffering from a disease against which the compounds areeffective, causes reduction, remission, or regression of the disease. A“subject” is a vertebrate, mammal, domestic animal or human being.

In the practice of this invention the “pharmaceutically acceptablevehicle” is any physiological vehicle known to those of ordinary skillin the art useful in formulating pharmaceutical compositions.

In one embodiment, the pharmaceutical vehicle may be a liquid and thepharmaceutical composition would be in the form of a solution. Inanother embodiment, the pharmaceutically acceptable vehicle is a solidand the composition is in the form of a powder or tablet. In a furtherembodiment, the pharmaceutical vehicle is a gel and the composition isin the form of a suppository or cream. In a further embodiment thecompound or composition may be formulated as a part of apharmaceutically acceptable transdermal patch.

A solid vehicle can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the vehicle is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with avehicle having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid vehicles include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid vehicles are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidvehicle such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid vehicle can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid vehicles fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the vehicle can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid vehicles are useful insterile liquid form compositions for parenteral administration. Theliquid vehicle for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Vehicles are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

The compounds of general formula I can be administered orally in theform of a sterile solution or suspension containing other solutes orsuspending agents (for example, enough saline or glucose to make thesolution isotonic), bile salts, acacia, gelatin, sorbitan monoleate,polysorbate 80 (oleate esters of sorbitol and its anhydridescopolymerized with ethylene oxide) and the like.

A compound of general formula I can also be administered orally eitherin liquid or solid composition form. Compositions suitable for oraladministration include solid forms, such as pills, capsules, granules,tablets, and powders, and liquid forms, such as solutions, syrups,elixirs, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions, and suspensions.

The compounds may be combined with a pharmaceutically acceptable vehicleand another therapeutically active agent prior to administration. Theother therapeutically active agent may be for the treatment ofparkinsonism (including Parkinson's disease).

In another embodiment of the present invention, the compound maycombined with a pharmaceutically acceptable vehicle and anothertherapeutically active agent, wherein such agent is an antipsychoticagent used for the treatment of psychoses, prior to administration.

The invention will be illustrated further by Example and with referenceto the following drawings, in which:

FIG. 1 is a graphical representation of parkinsonian disability (FIG.1A) and dyskinesia (FIG. 1B) timecourses following levodopaadministration in MPTP-lesioned marmosets in the presence and absence oftopiramate.

FIG. 2 is a graphical representation of additive parkinsonian disability(FIG. 2A) and dyskinesia (FIG. 2B) following levodopa administration inthe time period 0-1 hours post administration in MPTP-lesioned marmosetsin the presence and absence of topiramate.

FIG. 3 is a graphical representation of additive parkinsonian disability(FIG. 3A) and dyskinesia (FIG. 3B) following levodopa administration inthe time period 1-2 hours post administration in MPTP-lesioned marmosetsin the presence and absence of topiramate.

FIG. 4 is a graphical representation of additive parkinsonian disability(FIG. 4A) and dyskinesia (FIG. 4B) following levodopa administration inthe time period 2-3 hours post administration in MPTP-lesioned marmosetsin the presence and absence of topiramate.

EXAMPLE 1

Topiramate Reduces L-DOPA-Induced Dyskinesia

The MPTP-Lesioned Primate:

1-methyl-4-phenyl-tetrahydropyridine (MPTP), when given to non-humanprimates, is selectively toxic to dopamine cells and produces an animalmodel of Parkinson's disease. The MPTP-lesioned primate represents thebest animal model of Parkinson's disease and L-DOPA-induced dyskinesia,the most common form of dyskinesia encountered in the clinicalsituation. The pathology, symptomatology and response of symptoms totreatments and production of side effects following treatment are verysimilar in the MPTP-lesioned primate to those seen in Parkinson'sdisease patients. Thus, when untreated, MPTP-lesioned primates showparkinsonian symptoms such as reduced range of movement, reduced speedof movement (bradykinesia) and an abnormal, hunched, parkinsonianposture. Of especial relevance to this invention is that, when treatedrepeatedly with L-DOPA, MPTP-lesioned primates develop the side effectof L-DOPA-induced dyskinesia in a way which is essentiallyindistinguishable from that seen in Parkinson's disease patients (Nash JE, et al., Exp Neurol 2000, 165:136-42; Kanda T, et al., Exp Neurol2000, 162:321-7; Bibbiani F, et al., Neurology 2001, 57:1829-34;Konitsiotis S, et al., Neurology 2000, 54:1589-95; Blanchet P J, et al.,J Pharmacol Exp Ther 1999, 290:1034-40; Hille C J, et al., Exp Neurol2001, 172:189-98; Henry B, et al., Exp Neurol 2001, 171:139-46; and FoxS H, et al., Mov Disord 2001, 16:642-50).

Preparation of MPTP-Lesioned Marmoset Model of Parkinson's Disease andL-DOPA-Induced Dyskinesia.

A study was performed on six adult marmosets (Callithrix jacchuis) toassess the ability of topiramate to reduce dyskinesia, specificallyL-DOPA-induced dyskinesia. The marmosets were rendered parkinsonian bysubcutaneous injection of 2 mg/kg MPTP for 5 consecutive days. Themarmosets were allowed to recover for 18 weeks until their parkinsonismwas stable. The degree of activity and disability before and after MPTPtreatment were assessed using a combination of scales that measurelocomotor activity, mobility, bradykinesia and posture (see below).Animals were treated with L-DOPA (12 mg/kg twice daily for 6 weeks) toprime them to elicit dyskinesia. The animals had received a variety ofpotential anti-parkinsonian therapies prior to the current study. Therewas a washout period of 2 weeks between completion of any other studyand the commencement of the current study.

Details of Drug Administration

Topiramate or vehicle was administered orally in a volume of 5 ml/kg viaa syringe in the animal's home cage. The animals were immediatelytransferred to an experimental cage (60 cm×55 cm×75 cm, with the perch25 cm from floor of cage) for behavioral assessment.

On each day all animals also received L-DOPA (15 mg/kg).

Assessment of Behavior

Behavior was assessed for 6 hours post drug administration.

A battery of behavioral tests was performed:

1) Dyskinesia—Non-Parametric Measures Based on the Following Scale:

Dyskinesia score: 0=Absent, 1=Mild, fleeting, present less than 30% ofthe observation period, 2=Moderate, not interfering with normalactivity, present more than 30% of the observation period, 3=Marked, attimes interfering with normal activity, present less than 70% of theobservation period, 4=Severe, continuous, replacing normal activity,present more than 70% of the observation period.

2) Parkinsonian Disability—Non-Parametric Measures Based on theFollowing Scales:

-   -   a) Range of movement score: 0=no movement, 1=movement of head on        the floor of the cage, 2=movement of limbs, but no locomotion,        on the floor of the cage, 3=movement of head or trunk on wall of        cage or perch, 4=movement of limbs, but no locomotion, on wall        of cage or perch, 5=walking around floor of cage or eating from        hopper on floor, 6=hopping on floor of cage, 7=climbing onto        wall of cage or perch, 8=climbing up and down the walls of the        cage or along perch, 9=running, climbing between cage        walls/perch/roof, uses limbs through a wide range of motion and        activity. The score given was the maximum achieved in each 10        minute observation period.    -   b) Bradykinesia score: 0=normal speed and initiation of        movement, 1=mild slowing of movement, 2=moderate slowing,        difficulty initiating and maintaining movement, marked freezing,        3=akinetic, unable to move, with prolonged freezing episodes.        The score given was representative of behaviour over the        observation period.    -   c) Postural abnormality score: 0=normal, upright, holds head up,        normal balance, 1=abnormal, crouched, face down, may lose        balance. The score given was representative of behaviour over        the observation period.    -   d) Parkinsonian disability score: A combination of the mobility,        bradykinesia and posture scores according to the formula        [18−(Range of movement*2)+(Bradykinesia*3)+(Posture*9)] to give        a global parkinsonian disability rating.

Behavioral tests 1 and 2 (dyskinesia and parkinsonian disability,respectively) were assessed for 10 minutes every 30 minutes over thecourse of 3 hours, by post hoc analysis of video-recordings by anobserver blinded to the treatment. The score given/achieved in each 10minute time period was presented as defined above.

The results are shown in FIGS. 1A and 1B. FIG. 1A: Each data pointrepresents the median score from the group of animals (n=6). The Y-axisis labeled such that parkinsonian disability scores are presented as 0(none), 9 (mild), 18 (moderate), 27 (marked) and 36 (severe). FIG. 1B:Each data point represents the median score from the group of animals(n=6). The Y-axis is labeled such that dyskinesia scores are presentedas 0 (none), 1 (mild), 2 (moderate), 3 (marked) and 4 (severe).

Analysis of Dyskinesia Data

Data were collected for each one hour time period for severity ofdyskinesia and were analyzed with a Wilcoxon matched pairs test (thesoftware used was Prism version 3.0, GraphPad Software Inc). The resultsshown in FIGS. 2, 3, and 4 show the effect of topiramate treatment onMPTP-lesioned marmosets following levodopa treatment in the time period0-1, 1-2 hours, and 2-3 hours hours post administration, respectively.

The results further demonstrate that following administration oftopiramate and L-DOPA, less dyskinesia was seen in comparison to L-DOPAalone.

FIG. 2 shows the additive parkinsonian disability (FIG. 2A) anddyskinesia (FIG. 2B) following levodopa administration in the timeperiod 0-1 hours post administration in MPTP-lesioned marmosets in thepresence or absence of topiramate. FIG. 2A: Data are presented asindividual data from each animal, with a median for the group(horizontal line). Parkinsonian disability scores were calculated bycumulating both scores obtained in each one hour period (maximum 72).The Y-axis is labeled such that parkinsonian disability scores arepresented as 0 (none), 9 (mild), 18 (moderate), 27 (marked) and 36(severe). Data were analyzed using the Wilcoxon matched paired test,P>0.05. FIG. 2B: Data are presented as individual data from each animal,with a median for the group (horizontal line). Dyskinesia scores werecalculated by cumulating both scores obtained in each one hour period(maximum 72). The Y-axis is labeled such that dyskinesia scores arepresented as 0 (none), 1 (mild), 2 (moderate), 3 (marked) and 4(severe). Data were analyzed using the Wilcoxon matched paired test,*P<0.05.

FIG. 3 shows the additive parkinsonian disability (FIG. 3A) anddyskinesia (FIG. 3B) following levodopa administration in the timeperiod 1-2 hours post administration in MPTP-lesioned marmosets in thepresence or absence of topiramate. Details of FIGS. 3A and 3B are thesame as FIGS. 2A and 2B.

FIG. 4 shows the additive parkinsonian disability (FIG. 4A) anddyskinesia (FIG. 4B) following levodopa administration in the timeperiod 2-3 hours post administration in MPTP-lesioned marmosets in thepresence or absence of topiramate. Details of FIGS. 3A and 3B are thesame as FIGS. 3A and 3B except that in FIG. 4B the analyzed data had aWilcoxon matched paired test value of P>0.05.

The Wilcoxon matched pairs test is a nonparametric test to compare twopaired groups. It is also called the Wilcoxon matched pairs signed rankstest. The Wilcoxon test analyzes only the differences between the pairedmeasurements for each subject. The P value answers this question: If themedian difference really is zero overall, what is the chance that randomsampling would result in a median difference as far from zero (or moreso) as observed in this experiment? If the P value is small, you canreject the idea that the difference is a coincidence, and concludeinstead that the populations have different medians. This is the case inthis example, P<0.05, (i.e., less than a chance of 1 in 20 that theresults are just coincidence).

The Wilcoxon test is the most appropriate statistical test forevaluating whether the differences between the levels of dyskinesia inthe animals are different when receiving topiramate as compared tovehicle with the current study design. All animal received bothtopiramate and vehicle. The Wilcoxon test computes the differencebetween the two values in each individual animal (one with topiramatethe other with vehicle) and analyzes the differences. The Wilcoxon testdoes not assume that those differences are sampled from a Gaussiandistribution, this is important as dyskinesia is a non-parametricstatistic, there is no guarantee that dyskinesia scores will bedistributed in a Gaussian manner.

The results demonstrate that following administration of topiramate andL-DOPA, less dyskinesia was seen in comparison to L-DOPA alone (FIGS.1B, 2B and 3B). They also demonstrate that while relieving dyskinesia,topiramate is without major effect on the anti-Parkinsonian action ofL-DOPA (FIGS. 1A, 2A, 3A, and 4A).

One skilled in the art will readily appreciate that the specific methodsand results discussed in the Example are merely illustrative of theinvention as described more fully in the claims.

REFERENCES

-   Bibbiani, F., et al., “Serotonin 5-HT1A agonist improves motor    complications in rodent and primate parkinsonian models” Neurology    57: 1829-34 (2001).-   Blanchet, P J, et al., “Differing effects of N-methyl-D-aspartate    receptor subtype selective antagonists on dyskinesias in    levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys” J    Pharmacol Exp Ther 290: 1034-40 (1999).-   Burne, et al; “The contribution of tremor studies to diagnosis of    Parkinsonian and essential tremor: a statistical evaluation” J Clin    Neurosci., 9(3): 237-242 (2002).-   Connor, G S, “A double-blind placebo-controlled trial of topiramate    treatment for essential tremor” Neurology 59(1): 132-134 (2002).-   Fox, S H, et al., “Neural mechanisms underlying peak-dose dyskinesia    induced by levodopa and apomorphine are distinct: evidence from the    effects of the alpha(2) adrenoceptor antagonist idazoxan” Mov Disord    16: 642-50 (2001).-   Henry, B., et al., “Mu- and delta-opioid receptor antagonists reduce    levodopa-induced dyskinesia in the MPTP-lesioned primate model of    Parkinson's disease” Exp Neurol 171: 139-46 (2001).-   Hille, C J, et al., “Antiparkinsonian action of a delta opioid    agonist in rodent and primate models of Parkinson's disease” Exp    Neurol 172: 189-98 (2001).-   Kanda T, et al., “Combined use of the adenosine A(2A) antagonist    KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists    increases antiparkinsonian activity but not dyskinesia in    MPTP-treated monkeys” Exp. Neurol. 162: 321-7 (2000).-   Konitsiotis, S., et al., “AMPA receptor blockade improves    levodopa-induced dyskinesia in MPTP monkeys” Neurology 54: 1589-95    (2000).-   Nash, J. E., et al., “Antiparkinsonian actions of ifenprodil in the    MPTP-lesioned marmoset model of Parkinson's disease” Exp. Neurol.    165: 136-42, (2000).

1-13. (canceled)
 14. A method of treating dyskinesia in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of the formula (I):

wherein X is Oxygen or CH₂; R₂, R₃, R₄ and R₅ are independentlyHydrogen, lower alkyl and R₂ and R₃ and/or R₄ and R₅ together may be agroup of the formula (II):

wherein R₆ and R₇ are the same or different and are Hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.
 15. The method of claim 14, wherein the compound is topiramate.16. The method of claim 14, wherein the dyskinesia is associated with abasal ganglia-related movement disorder.
 17. The method of claim 14,wherein the dyskinesia is associated with parkinsonism.
 18. The methodof claim 17, wherein the parkinsonism is idiopathic Parkinson's diseaseor post-encephalitic parkinsonism.
 19. The method of claim 14, whereinthe dyskinesia is associated with dopamine replacement therapy.
 20. Themethod of claim 14, wherein the dyskinesia is associated withoff-dystonia in Parkinson's disease.
 21. The method of claim 14, whereina therapeutically effective amount of a neuroleptic is also administeredto the subject.
 22. The method of claim 21, wherein the neuroleptic isselected from the group consisting of haloperidol, chlorpromazine,quetiapine, clozapine, trifluoperazine, metoclopramide and fluphenazine.23. The method of claim 14, wherein the dyskinesia is associated withHuntington's disease, idiopathic torsion dystonia, tardive dyskinesia,Tourette's syndrome, ballism, senile chorea.
 24. The method of claim 14,wherein the dyskinesia arises as a side-effect of a therapeutic agent.25. The method of claim 24, wherein the dyskinesia arises as aside-effect of the treatment of parkinsonism with a therapeutic agent.26. The method of claim 25, wherein the therapeutic agent is selectedfrom the group consisting of ropinirole, pramipexole, cabergoline,bromocriptine, lisuride, pergolide, L-DOPA and apomorphine.